Transformation of naproxen during the chlorination process: Products identification and quantum chemistry validation

The by-products produced by pharmaceutically active compounds (PhACs) during chlorination are attracting wide concern. Thus, the transformation and toxicity of naproxen (NAP) during the chlorination process were assessed in this study. The transformation of NAP was found to follow pseudo-first-order kinetics, and the first-order rate constant was improved by increasing the NaOCl dose. High-resolution mass spectrometry (HRMS) was successfully applied to identify 14 chlorination products. This study represents the first elucidation and report of the exact structure of the primary chlorine substitution product ((2S)-2-(5-chloro-6-methoxy-2-naphthyl)propionic acid) based on HRMS and ¹H NMR. Chlorine will primarily substitute the hydrogen atom on the C7 position of the naphthalene ring to form the mono-chlorine substitution product, as further validated at the theoretical level by quantum chemical calculations. A series of HOCl-induced reactions, including substitution, demethylation, and dehydrogenation, led to the transformation of NAP during the chlorination process. ECOSAR program revealed that the potential aquatic toxicity of the transformation products is significantly higher than that of the parent NAP. Their introduction into the environment may still pose potential risks.